Abstract P135: Abdominal Obesity is Associated With DNA Methylation in Cardiovascular Health Related Genes Among Adolescents

Abstract

Background: Obesity, especially abdominal obesity, is a risk factor for coronary artery disease (CAD) in various populations. Little is known regarding the role of epigenetics in the association between abdominal obesity and cardiovascular health in adolescents. Hypothesis: Abdominal and especially visceral obesity is associated with DNA methylation in genes related to cardiovascular health among adolescents. Methods: We used data from a sample of 263 adolescents participating in the population-based Penn State Child Cohort follow-up exam (N=421). Dual-energy X-ray absorptiometry was used to measure visceral and subcutaneous fat areas (VAT; SAT, in cm 2 ) in each participant. We extracted DNA from peripheral leukocytes and subjected it to enhanced, reduced representation bisulfite sequencing. A high-throughput assay provided single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions. We excluded bases with < 10x coverage or available from < 20 individuals. We analyzed a total of 1,609,424 methylation sites. We used linear regression models to assess the association between site-specific methylation level (expressed as %) and VAT and SAT. We adjusted all models for age, race, sex, and body mass index (BMI) percentile. We used Bonferroni-adjusted statistical tests to identify sites significantly related to VAT and separately, SAT. We mapped the VAT- and SAT-associated sites to the hg19 assembly and subjected them to Ingenuity Pathway Analysis (IPA) wherein mapped gene sets were examined for enrichment of downstream function and diseases. Results: On average, the sample was 55% male, 79% white and aged 16.7 (standard deviation = 2.2) years. VAT and SAT were significantly associated with methylation at 296 sites within 193 genes and 101 sites within 87 genes, respectively. Among them, seven genes related to VAT and five related to SAT were associated with CAD. IPA revealed that CAD-related genes were significantly enriched in both gene sets (for VAT: p=1.97x10 -2 ; SAT: p=9.67x10 -3 ). Genes related to VAT also were significantly enriched in endothelial activation (p=8.16x10 -3 ), fibrogenesis (p=5.01x10 -5 ), and dyslipidemia (p=7.99x10 -3 ). Indeed, higher VAT was associated with hypomethylation of CD14 and hypermethylation of GNMT , while higher SAT was associated with hypermethylation of ADRB1 and hypomethylation of TUBB4A . Conclusion: If externally validated, our data would suggest that (1) abdominal obesity in adolescence is associated with DNA methylation of genes related to cardiovascular health, independent of BMI; and (2) visceral adiposity has a more prominent association with cardiovascular health through DNA methylation of genes with roles in atherogenesis.